Chromatin Modifications by Methylation and Ubiquitination: Implications in the Regulation of Gene Expression

Saint Louis University School of Medicine and the Saint Louis University Cancer Center, St. Louis, Missouri 63104, USA.
Annual Review of Biochemistry (Impact Factor: 30.28). 02/2006; 75(1):243-69. DOI: 10.1146/annurev.biochem.75.103004.142422
Source: PubMed

ABSTRACT It is more evident now than ever that nucleosomes can transmit epigenetic information from one cell generation to the next. It has been demonstrated during the past decade that the posttranslational modifications of histone proteins within the chromosome impact chromatin structure, gene transcription, and epigenetic information. Multiple modifications decorate each histone tail within the nucleosome, including some amino acids that can be modified in several different ways. Covalent modifications of histone tails known thus far include acetylation, phosphorylation, sumoylation, ubiquitination, and methylation. A large body of experimental evidence compiled during the past several years has demonstrated the impact of histone acetylation on transcriptional control. Although histone modification by methylation and ubiquitination was discovered long ago, it was only recently that functional roles for these modifications in transcriptional regulation began to surface. Highlighted in this review are the recent biochemical, molecular, cellular, and physiological functions of histone methylation and ubiquitination involved in the regulation of gene expression as determined by a combination of enzymological, structural, and genetic methodologies.

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    • "The association between MED23 and RNF20/40 establishes a mechanistic link between the Mediator complex and epigenetic regulation during transcription, which may provide further insight into the roles that the Mediator complex plays in (i) crosstalk between multiple histone modifications, (ii) transcription elongation , (iii) histone modifications and cancer, and (iv) mRNA processing , as we discuss here. Firstly, previous studies regarding trans-histone modification crosstalk indicate that a strict linkage exists between ubiquitinated H2B and histone H3 methylation (Dover et al, 2002; Shilatifard, 2006; Kim et al, 2013; Wu et al, 2013). However, other studies suggest that H2Bub is independent of H3 methylation (Tanny et al, 2007; Lee et al, 2012). "
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    ABSTRACT: The Mediator complex orchestrates multiple transcription factors with the Pol II apparatus for precise transcriptional control. However, its interplay with the surrounding chromatin remains poorly understood. Here, we analyze differential histone modifications between WT and MED23(-/-) (KO) cells and identify H2B mono-ubiquitination at lysine 120 (H2Bub) as a MED23-dependent histone modification. Using tandem affinity purification and mass spectrometry, we find that MED23 associates with the RNF20/40 complex, the enzyme for H2Bub, and show that this association is critical for the recruitment of RNF20/40 to chromatin. In a cell-free system, Mediator directly and substantially increases H2Bub on recombinant chromatin through its cooperation with RNF20/40 and the PAF complex. Integrative genome-wide analyses show that MED23 depletion specifically reduces H2Bub on a subset of MED23-controlled genes. Importantly, MED23-coupled H2Bub levels are oppositely regulated during myogenesis and lung carcinogenesis. In sum, these results establish a mechanistic link between the Mediator complex and a critical chromatin modification in coordinating transcription with cell growth and differentiation. © 2015 The Authors.
    The EMBO Journal 09/2015; DOI:10.15252/embj.201591279 · 10.43 Impact Factor
    • "Here, we report PAF1 as being an evolutionarily conserved factor that contributes significantly to the process of pause release by Pol II. PAF1 was originally identified biochemically as a factor co-purifying with Pol II from yeast extracts (Shi et al., 1996; Wade and Jaehning, 1996), and the role of PAF1 and its complex, in serving as a platform for co-transcriptional histone-modifying enzymes and RNA-processing factors, is highly conserved from yeast to humans (Krogan et al., 2003; Shilatifard 2006). Our studies in mammalian cells reveal that the loss of PAF1 leads to widespread release of the promoter-proximal paused Pol II into gene bodies. "
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    ABSTRACT: The control of promoter-proximal pausing and the release of RNA polymerase II (Pol II) is a widely used mechanism for regulating gene expression in metazoans, especially for genes that respond to environmental and developmental cues. Here, we identify that Pol-II-associated factor 1 (PAF1) possesses an evolutionarily conserved function in metazoans in the regulation of promoter-proximal pausing. Reduction in PAF1 levels leads to an increased release of paused Pol II into gene bodies at thousands of genes. PAF1 depletion results in increased nascent and mature transcripts and increased levels of phosphorylation of Pol II's C-terminal domain on serine 2 (Ser2P). These changes can be explained by the recruitment of the Ser2P kinase super elongation complex (SEC) effecting increased release of paused Pol II into productive elongation, thus establishing PAF1 as a regulator of promoter-proximal pausing by Pol II. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 08/2015; 162(5). DOI:10.1016/j.cell.2015.07.042 · 32.24 Impact Factor
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    • "H2Bub1 can modulate chromatin structure and DNA accessibility to regulate diverse DNA-dependent processes such as gene transcription (Zhang, 2003; Shilatifard, 2006; Pinder et al., 2013). RNA interference against human RNF20/RNF40 leads to reduced H2Bub1 and subsequent repression of HOX gene expression (Zhu et al., 2005). "
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    ABSTRACT: Histone H2B monoubiquitination (H2Bub1) is an important regulatory mechanism in eukaryotic gene transcription and is essential for normal plant development. However, the function of H2Bub1 in reproductive development remains elusive. Here, we report OsHUB1 (Oryza sativa HISTONE MONO-UBIQUITINATION1) and OsHUB2, the homologues of Arabidopsis HUB1 and HUB2 proteins which function as E3 ligases in H2Bub1, are involved in late anther development in rice. oshub mutants exhibit abnormal tapetum development and aborted pollen in postmeiotic anthers. Knock-out of OsHUB1 or OsHUB2 results in the loss of H2Bub1, and a reduction in the levels of dimethylated lysine 4 on histone 3 (H3K4me2). Anther transcriptome analysis revealed that several key tapetum degradation-related genes including OsC4, OsCP1 and UDT1 were down-regulated in the mutants. Further, chromatin immunoprecipitation assays demonstrate that H2Bub1 directly targets OsC4, OsCP1 and UDT1 genes and enrichment of H2Bub1 and H3K4me2 in the targets is consistent to some degree. Our studies suggest that histone H2B monoubiquitination, mediated by OsHUB1 and OsHUB2, is an important epigenetic modification that in concert with H3K4me2 modulates transcriptional regulation of anther development in rice. Copyright © 2015, American Society of Plant Biologists.
    Plant physiology 07/2015; 168(4). DOI:10.1104/pp.114.256578 · 6.84 Impact Factor
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